The present invention relates to the use of thymosin alpha 1 in combination with dacarbazine and optionally Interferon alpha, for preparing a medicament for the treatment of malignant melanoma on stage IV.
Melanoma is a malignant tumor of melanocytes, which are cells derived from the neural crest.
Melanomas are found primarily in normal areas of the skin, but may also occur in other mucosal surfaces.
Skin nevi may be suspected of undergoing malignant changes if they appear darker or have variable discoloration, or there is itching, an increase in size, or development of satellites.
Melanoma is unusual in that it is far more likely to metastasize than other types of cancer and can spread to regional or distant lymph nodes, or to any of the major organ systems of the body.
The most common sites of metastasis other than the skin are the lung, liver, brain, and lymph nodes.
The clinical presentation of stage IV malignant melanoma (“high-risk melanoma” or “H-RM”) will vary depending on the stage and site(s) of systemic involvement.
Melanoma occurs more frequently in males and is found in adults of all ages.
The American Cancer Society (“ACS”) estimated the number of new cases of all skin melanomas for 2005 at 59,580 and the number of deaths at 7,770.
HR-M accounts for approximately 22% of all cutaneous malignant melanoma cases and is associated with a high mortality rate.
Several risk factors have been identified for melanoma. It has long been believed that exposure to sunlight (i.e., ultraviolet radiation) is the primary etiological factor in the development of melanoma, which is consistent with higher incidence rates in populations with less photoprotective melanin that live closer to the equator.
Other known risk factors for melanoma include: genetics, where 5-10% of melanoma patients have a family history of the disease; dysplastic/atypical nevi; complexion (fair-skinned, red-headed or blond individuals, and individuals with a high tendency to freckle are at higher risk for developing melanoma); and history of severe blistering sunburn.
Patients diagnosed with H-RM have a strikingly worse prognosis than patients whose tumor are of minimal thickness/invasion and are locally confined.
A number of key clinical factors have been identified as prognostic indicators for melanoma, including: age; sex; characteristics of the primary tumor (e.g., anatomic location, size, Clark's level, Breslow's thickness, histopathological type, ulceration, inflammatory reaction); and lymph node involvement.
H-RM is generally a fatal disease due to the absence of adequate therapeutic options.
H-RM is characterized by tumors of the skin that metastasize to virtually every organ. The clinical presentation of H-RM varies according to the stage and site(s) of systemic involvement.
Early stage malignant melanoma without metastasis is treated by wide field surgical excision and has a high cure rate. While regional lymph node removal in addition to wide field surgical excision of the primary tumor may be successful in Stage III malignant melanoma.
In stage IV malignant melanoma, characterized by distant unresectable metastases, there is no currently available treatment. Once the metastatic process has started, the tumor becomes increasingly resistant to current methods of therapy.
Thymosin alpha 1 is a compound well known in the medical field.
Subcutaneous administration of 1 or 10 mg per day of thymosin alpha 1 to nude mice previously inoculated with human non-small cell lung cancer (“NSCLC”) cells significantly decreased tumor volume.
Pulmonary metastases in mice with methylcholanthrene-induced fibrosarcoma were also reduced by thymosin alpha 1, and local sarcoma growth as well as liver and lung metastases of lymphosarcoma cells were significantly reduced in BALB/c mice treated with thymosin alpha 1.
In Int. J. Immunopharmacol. 2000; 22:1067-76 two experiences are reported:
1) The use of Dacarbazine (DTIC) (850 mg/m2 i.v. on day 1)+thymosin alpha 1 (2 mg s.c. on days 4-7) in combination with interleukin-2 (18 MU/m2 i.v. on days 8-12). Each cycle lasted 21 days.
2) The use of DTIC (200 mg/m2 i.v. on days 1-4)+thymosin alpha 1 (1 mg s.c. on days 8-11 and 15-18) in combination with interferon alpha (3 MIU i.m. on days 11 and 18). Each cycle lasted 28 days.
These experiences showed that these treatments enhance the host immune response in patients with H-RM and prolong their survival.
Annals of Oncology. 1994; 5:741-46, relates to the use of dacarbazine (850 mg/m2 i.v. on day 1) in combination with thymosin alpha 1 (2 mg s.c. on days 4-7) and IL-2 (18 MIU i.v. on days 8-12) in patients with H-RM. Each cycle lasted 21 days.
Favalli (1993; Combination Therapy in Malignant Melanoma. Third International Symposium on Combination Therapies, Houston, Tex.: Institute for Advance Studies in Immunology & Aging) teaches about the use of thymosin alpha 1 (1 mg s.c. on days 8-11 and 15-18) in combination with dacarbazine (200 mg/m2 i.v. on days 1-4) and IFN-α (3 MIU i.m. on days 11 and 18) in patients with malignant melanoma. Each cycle lasted 28 days.
Current development of alternative therapies for H-RM is directed toward immunotherapies. Adjuvant immunotherapy agents designed to augment the immune response are under development and include melanoma vaccines, interferons (“IFNs”), interleukin-2 (“IL-2”), and tumor-infiltrating lymphocytes, and plasmid-based DNA vaccines.
Trials are being conducted to evaluate alternative immunotherapy agents in patients with H-RM have generally yielded less than encouraging results (Cancer Inves. 23:323-37; 2005). In general, large randomized trials have not provided any evidence of significant clinical benefit, despite the initial promising results.
While the annual incidence of malignant melanoma is on the rise, long-term studies demonstrate that current therapeutic options, for malignant melanoma on stage IV characterized by distant unresectable metastases, only produce limited results with little impact on the patient's overall survival.
Trials conducted with the interferons and interleukins in combination with dacarbazine have not demonstrated a clinical advantage over decarbazine monotherapy in advanced melanoma. Immunotherapeutic agents in combination with lymphokine-activated lymphocytes have not been found to improve response rates or affect durable remissions.
DTIC is currently the only chemotherapeutic agent approved for use in metastatic melanoma. The efficacy of dacarbazine in the treatment of metastatic melanoma is very dependent on disease site and, according to the most recent publications and abstracts (Journal of Clinical Oncology and ASCO annual meeting proceedings, 2004), the actual overall responses to DTIC are 5.5-6.8%, with responses being short-lived (i.e., three to six months). There is no evidence that these responses have any effect on the patients' overall survival.
Other drugs investigated for use alone or in combination with dacarbazine, include: alkylating agents and nitrosureas; vinca alkaloids; platinum compounds; hormonal agents; and plant-derived agents (paclitaxel (TAXOL), coumarin). None of these drugs, either alone or in combination with dacarbazine and/or Interferon alpha have been shown to be any more effective than dacarbazine alone (Cancer Medicine, Ed. 5 2000; pp. 1849-69) and are considered useful only for symptomatic relief.
In the medical field there is a pressing need to develop new therapies for stage IV malignant melanoma characterized by distant unresectable metastases.
As above mentioned to date, DTIC is currently the only chemotherapeutic agent approved for use in metastatic melanoma. The actual overall responses to DTIC are 5.5-6.8%; and there is no evidence that these responses have any effect on the patients' overall survival.
To date, the use of thymosin alpha 1 (a) in a dose higher than 1 mg/s.c. in combination with dacarbazine and/or Interferon alpha; for preparing a medicament for the treatment of malignant melanoma on stage IV characterized by distant unresectable metastases, was not known in the art.